Improved Safety Profile of Capecitabine as Adjuvant Therapy Mirrors Metastatic Setting

August 1, 2003

This special supplement to Oncology News International includes 28 reportswith updated information on clinical trials investigating capecitabine and other agents inthe treatment of advanced colorectal and breast cancers, and other solid tumors.The reports summarize selected presentations from the 39th Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) and related educational symposiaheld in conjunction with ASCO.

BRADFORD, United Kingdom-Oral capecitabine (Xeloda) has an improvedsafety profile as adjuvant therapyfor Duke's C colon cancer compared withIV fluorouracil (5-FU)/leucovorin, theMayo Clinic regimen, according to a studyreported by Chris Twelves, MD, Universityof Leeds and Bradford, United Kingdom(ASCO abstract 1182). This improvedsafety profile of capecitabine inthe adjuvant setting mirrors that reportedin the metastatic setting, he added."These results are part of a plannedsafety analysis that was conducted 18months after enrollment of the last patienton a phase III trial of capecitabine vsbolus 5-FU/leucovorin as adjuvant therapyfor colon cancer (the X-ACT study),"Dr. Twelves said."The results of the safety analysis demonstratedthat oral capecitabine, as adjuvanttreatment for Duke's C colon cancer,was associated with significantly less diarrhea,nausea and vomiting, stomatitis,alopecia, and grade 3/4 neutropenia," headded.Adjuvant IV 5-FU/leucovorin improvesoutcomes in colon cancer. Capecitabinedoes too, but it is a tumor-activatedoral fluoropyrimidine. "Two large phaseIII studies demonstrated that capecitabineachieves superior activity and improvedsafety compared with IV 5-FU/leucovorin as first-line therapy for metastaticcolorectal cancer," Dr. Twelves reported.Oral Therapy PreferredThe oral administration of capecitabineenables twice-daily dosing that mimicscontinuous infusion 5-FU. "Of particularimportance is the fact that 9 out of 10patients prefer oral chemotherapy to IVadministration," Dr. Twelves noted."Outpatient oral chemotherapy allows patientsto live a more normal life whilereceiving adjuvant treatment. This activity and patient preference for oral chemotherapyjustifies comparing capecitabinewith 5-FU/leucovrin as adjuvant treatmentof Dukes'C colon carcinoma."Phase III X-ACT TrialThe X-ACT trial was an open-label,multinational, randomized, parallelgroup,phase III trial of adjuvant therapyfor Duke's C colon cancer. Between November1998 and November 2001, 1,987patients were enrolled at 164 centersworldwide. The primary end point of thetrial was noninferiority in disease-freesurvival, and secondary end points were3-year survival, safety profile, and qualityof life. To determine the safety profile,safety was continuously monitored duringtreatment plus 28 days afterwards inall patients who received at least one doseof study medication (n = 1,970).The baseline characteristics were wellbalanced in the two treatment arms. Forexample, the median age in the capecitabinegroup was 62, and in the 5-FU/leucovoringroup, it was 63.Both groups experienced a similar lowincidence of treatment-related withdrawals.Eighty-two percent of patients receivingcapecitabine completed all eight cyclesand 88% of patients on 5-FU/leucovorin received all six cycles.In both groups, the median delivereddose per cycle was greater than 95% of theplanned dose throughout the treatment.Fewer patients in the capecitabine armrequired dose reductions due to adverseevents (41% with capecitabine vs 44%with 5-FU/leucovorin).Fewer Dose ReductionsOverall, fewer adverse events occurredin the capecitabine arm than in the 5-FU/leucovorin arm (4,158 vs 4,665, respectively).There were fewer treatment-relatedgrade 3/4 adverse events in the capecitabinearm than in the 5-FU/leucovorinarm (533 vs 560). There was significantlyless stomatitis and neutropenia in thecapecitabine arm, a low incidence of nauseaand vomiting (3%) in both arms, andless neutropenia in the capecitabine arm.Dr. Twelves did note that "hand-footsyndrome was significantly more commonwith capecitabine, but it can be easilymanaged with dose interruption and whennecessary, with dose modification." Hesaid that hyperbilirubinemia was morecommon with capecitabine, but that thisis a known side effect of fluoropyrimidinesand is rarely associated with clinicalor enzymatic abnormalities.Three treatment-related deaths occurredin the capecitabine arm vs four inthe 5-FU/leucovorin. There was a low incidenceof all-cause, 60-day mortality: five(0.5%) deaths in the capecitabine armand four (0.4%) in the 5-FU/leucovorinarm.Dr. Twelves concluded a descriptionof the safety analysis by stating, "Therewere fewer adverse events with capecitabinethan with 5-FU/leucovorin, andcapecitabine was associated with fewerlife-threatening adverse events. The improvedsafety profile of capecitabine inthe adjuvant setting mirrors that in themetastatic setting. A notable difference inthe capecitabine safety profile in the adjuvantand metastatic settings is less nausea/vomiting in the adjuvant setting, suggestingthat increased nausea/vomiting in themetastatic setting is disease-related."